Nobel dude

Kary Mullis revolutionized genetic research but thumbs his nose at the scientific establishment. It thumbs its nose right back.

Published March 29, 2000 5:00PM (EST)

"Take all the MVPs from professional baseball, basketball and football. Throw in a dozen favorite movie stars and a half-dozen rock stars for good measure, add all the television anchor people now on the air and collectively we have not affected the current good or the future welfare of mankind as much as Kary Mullis." -- Ted Koppel, on ABC's "Nightline"

At the Inventors Hall of Fame, Kary Mullis' work stands with that of Louis Pasteur and Guglielmo Marconi. Every research university in the country has tens, if not hundreds, of the machines that run on his ideas. Somewhere in Mullis' home is a round medal with a bas-relief of Alfred Nobel, representing the highest honor in science, one shared by the likes of Albert Einstein, James Watson and Francis Crick.

That's because Mullis invented the polymerase chain reaction, or PCR, a technique that makes a billion copies of one tiny gene, thereby allowing scientists to study that gene in great depth. As the historic Human Genome Project pulls into its home stretch, physics passes on to biology the mantle of most revolutionary science. In the last century we conquered the atom; now we will conquer the gene. And we will do it with PCR.

So Mullis must be an august man, writing his memoirs at the National Academy of Sciences, receiving policy makers and reverent fellow scientists in his book-lined study the way Papa Einstein did, right?

No way, dude! Mullis is like hangin' 10 in La Jolla, surfin' every day, brewskies in the fridge, LSD whenever. (Hey, he knows how to make the stuff.) Aliens occasionally visiting. A sexy new wife (since all the women at scientific conferences finally got sick of his lechery). And he just had a book published with his naked bod on the cover. Far out!

Actually, neither of these descriptions is accurate.

But the second one, Mullis as the surfer loon, is the most pervasive. I first heard about it two years ago at a bar during a conference in Southern California. Two geneticists were joking about how they should go find Mullis, do some drugs and score some chicks.

"Isn't he the guy who invented PCR?" I asked, surprised. Usually scientists are more respectful of their best and brightest. They said, yeah, Mullis may have invented PCR, but all those drugs, and all that womanizing, and all those crazy ideas about mind expansion had essentially placed his reputation in the alleyway trash bin, but he was fun to joke about.

When Mullis won the 1993 Nobel Prize in chemistry, journalists reinforced this stark morality tale: Boy genius invents a great thing but then behaves so irresponsibly that everyone laughs him out of science's good graces.

With his own book, "Dancing Naked in the Mind Field," published in 1998, Mullis fumbles the chance to show the world he isn't a fool. His writing is not thoughtful enough to justify his eccentricities, and the book makes him seem the jester people say he is. He writes, among other things: O.J. Simpson was innocent and Marcia Clark's a hottie, humans don't contribute to global warming and HIV is not the cause of AIDS. He purports to have found astral planes by scientific method, he relishes old tales of seducing women and taking drugs and he pooh-poohs current science.

"I'd put 90 percent of our present expenditure for physics and space technology on [finding asteroids that might hit Earth]," he writes. "The other 10 percent should go to looking for aliens." All of this is too challenging to simply glide over; and the lack of deeper explanations makes the man seem facile.

When I tracked down Mullis for an interview (his first for a major magazine in almost two years), I was primed to get some of those juicy "No way, dude; let's do some LSD!" quotations to jazz up my profile. Of course, character being different from caricature, I didn't get any.

During our hour-long phone conversation, Mullis spoke nothing like the bar-stool imitations of him I have heard scientists do. He has a soft voice that retains the diphthongal calm of his native South Carolina. It is indeed a good voice for a successful womanizer, but I was struck more by his consideration in answering my questions. His speech had none of the silly jumpiness of his book. I asked him why so many scientists dislike him.

"I'm not driven by being understood," he told me without raising his voice. "I don't try to be contrary, either. If I say, 'Hey, there's no reason to think that human beings have any long-term control over the weather,' I am telling you what I know. No one contradicts me honestly; they just shout because they dislike what I say."

He means what he says; it's important to him. He has ideas that belong on astral planes. But there is also passion -- the energy of a wide-ranging mind that disregards barriers of inquiry most of us heed. And there is hurt for being laughed at by the same scientists who have built their careers on PCR, the invention he gave them.

Mullis grew up in Columbia, S.C., in the late '40s and '50s. He showed a prodigal ability to blow things up: He gassed his grandmother (not lethally), and he torched some trees. At the time, he told me, he considered explosions part of a normal boyhood, and he laments the fact that today, "You can't ask your pharmacist to stock larger quantities of potassium nitrate because you want to make a bigger rocket."

Through Georgia Tech and graduate work at the University of California at Berkeley in the late '60s, Mullis mixed things well. He was creative and exacting in his work because he loved chemicals and catalysts. He was creative and expansive in his personal life because he loved sex and substances.

One of his thesis advisors at the time, Henry Rapaport, remembers that he was in love with learning; he took so many classes, both in and out of science, that his advisors had to be taskmasters in getting him to finish. Rapaport, who wonders if he might otherwise have stayed forever, also notes that Mullis was "attracted to the obscure and unusual."

It was at Berkeley that he learned to make LSD, and though he wouldn't talk with me about it, a clear theme across the anecdotes in his book is that he likes it still. To him it is indeed a mind-expanding substance.

It doesn't help his image that Mullis looks like a cross between David Letterman and Gene Wilder. His eyes smirk at the world. It's not hard to imagine him smirking his way through his first marriage, through at-home experiments in which he tried to turn off lights by wiring himself into an electrical circuit and then "willing" the lights off, through the seduction of nurses from his wife's medical school with this trick, through suggesting to the queen of Sweden at the Nobel ceremony that his son marry her daughter (she declined) and through the writing of his book, which begins -- in a preemptive strike against those who will laugh at the rest of what he has to say -- with the invention of PCR.

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He was smirking through the windshield of his Honda on a windy road in Northern California late on a Friday evening in May 1983. His girlfriend was in the seat next to him, and they were on their way to a romantic red-wine weekend for two. He held a job at the time in a small biotech company called Cetus, which had been founded by, among others, Carl Djerassi, the inventor of the birth control pill. As he drove, his mind was debriefing after a tough day in the lab. His work at Cetus involved DNA, and, like everyone who worked with DNA in the early '80s, he wanted to be able to make more of it, to get it to copy itself in a lab so he could study and manipulate it. Watson and Crick had shown that DNA is the recipe for life; scientists were desperate for an easy way to read it.

Part of his work involved now archaic ways of getting genes to replicate -- it took months and was heavily error prone. There must be a better way.

The muse descended, the idea came, Mullis pulled over. He searched the car for paper and pen and started writing, despite complaints from the girlfriend that they should go on to the house first. It was so easy, such an elegant idea, simple and effective. The polymerase chain reaction "was a chemical procedure," Mullis later wrote, "that would make the structures of the molecules of our genes as easy to see as billboards in the desert and as easy to manipulate as Tinkertoys."

Genes are double strands of chemicals, and the whole kit and caboodle of them, the entire recipe for life, is made of just four chemicals: adenine, thymine, cytosine and guanine. Think of each strand as a long string of these chemicals lined up in a row like beads. When two strands of DNA come together to make the familiar spiral-staircase helix (which graces the letterhead of so many biotech companies), these four chemicals get very picky: adenine (A for short) will only line up across from thymine (T) on the other strand. You never see two A's or an A across from cytosine (C) or guanine (G). C and G likewise form an exclusive pair.

Here's PCR in a nutshell: Put the gene you want to look at in a pipette with a little liquid. Heat it up and the double-stranded helix breaks apart. Each string of chemical beads drifts off by itself. Throw in a large and random assortment of loose A's, T's, C's and G's, and the individual chemical beads will seek out their pairs on the single strands. Once every chemical letter on each original strand has a new partner bead (the same-letter partner it always has because of chemical exclusivity), you cool down the mixture and the new rows of partner beads anneal into strands of their own, conveniently providing a new half to each original strand.

The helix reforms and -- voil`! -- you've made two exact copies of the one gene you started with. Heat these two up and you have four separate strands. Throw in more loose chemical letters, let them pair up and you have four identical genes. Repeat this process 30 times and you have more than a billion copies of that one piece of DNA you started with -- cartloads of it in lab terms.

So begins the genetic revolution. Without PCR, genetics is like trying to do experiments on one droplet of milk sitting on a white plate. The milk is hard to find, and you only have enough of it to try one thing -- such as add a droplet of orange juice and see what happens -- and that's it. You are limited in experimenting if you only have a tiny amount to play with. PCR makes genes by the milk pail, and scientists are thrilled.

Take Anne Blackwood, an oncologist at the University of Pennsylvania in Philadelphia who treats breast cancer patients and runs a lab looking for a cure. Cancer is caused by the slow accumulation of mutations in the genes of cells. To get any real sense of what's going on in the earliest stages of cancer, when only a few cells are worth looking at, Blackwood needs PCR to multiply the mutated genes.

Blackwood is also developing a long-term database of breast cancer types. She has a library of microscope slides of tissue biopsies -- tiny samples, some of them more than 10 years old. Using PCR, she can tease out the genetic profiles of each tissue sample and make a record of the mutations she sees. Such a large, statistical study of how cancer works is rapidly improving prognostic capabilities. It is also getting doctors much closer to a genetics-based cure.

Genetics-based cures are the Holy Grail of the Human Genome Project, the research that is mapping out all the genes in the human recipe book. Such mapping requires incredible amounts of gene replication; without PCR, it simply wouldn't be feasible.

Since PCR is ubiquitous in all pursuits "genetic," it is worth listing a few more: A hair left at a crime scene can find its owner through PCR. By the same token, DNA evidence, readable through PCR, has exonerated more than 60 innocent people on death row. (Mullis likes this one: "It always gives me a boost when some poor bastard that's been in there for 10 years is set free.")

President Clinton was discovered on a blue Gap dress, big boy writ large through PCR. Evolutionary biologists recently proved through genetics that hippos and dolphins are more closely related than hippos and pigs, despite fossil evidence to the contrary. Humans share just shy of 100 percent of our genes with chimpanzees -- we are minimally different items. Lettuce and humans share 40 percent; lettuce and mushrooms share less.

Astrobiologists haven't used PCR yet; but scientists at the National Aeronautics and Space Administration have launched a probe to bring dust from the tail of a comet back to Earth. If they find microbes in that stardust, they will run it through a PCR machine to see whether life on Earth was seeded by a comet.

Indeed, Ted Koppel and the rock stars cannot match PCR, and it is good of him to admit it. Neither can most living scientists, and yet they are not so generous. Why the sidelining, why the laughter? Why must Mullis wear the dunce cap? It depends, of course, on whom you ask.

Rapaport thinks it's Mullis' ego. Rapaport, who had close ties to Cetus, does not dispute that Mullis invented PCR on a roadside in Northern California -- in a sense. But, he says, science hates the "Hollywood hero," the notion that one person creates something complete at the moment of "Eureka!" What Mullis had, says Rapaport, was a theory, nothing more. From there, it took a handful of arguably equal intellects at Cetus months of hard work to take Mullis' notion and create a real PCR, one workable enough for the Blackwoods of the world to do something with. "Reduction to practice distinguishes the brilliant idea from malarkey," says Rapaport.

As for malarkey, says Dan Koshland, a famous Berkeley scientist who knew Mullis, look at everything else he's done. It's fine for a chemist to agitate about matters chemical, but when he sticks his nose into AIDS and global warming, he has crossed boundaries of professional knowledge that should be respected, Koshland says.

And the problem is his prize: He can't be ignored. "He was a free spirit before he got the Nobel Prize," Koshland says. "Now he's a free spirit with a Nobel Prize." And that's just tiresome: "His views on social issues are irrelevant."

"In the scientific community, there's a great deal of mutual respect for everybody, the realization that every worthwhile invention is a series of small steps taken by many people," says Rapaport.

Of course, the Nobel committee singles out scientists, and Mullis was very happy to be glorified all by himself, Rapaport says. Whereas most scientists do a less eloquent version of Isaac Newton's "If I have seen further it is by standing on the shoulders of Giants," Mullis' book mentions only bitterness toward those at Cetus who tried to take some credit for PCR. Rapaport notes, "If he'd been on a desert island, he wouldn't have come up with it."

Rather than protect Mullis' eccentricities, scientists mock them. But there is more to it than that: There are plenty of scientists, Nobel winners and others, who enjoy splendid suites on the top floor of the academy even though their kahuna-size egos prevent them from acknowledging that anyone might have helped them in that one great thing they invented once upon a time. So Mullis' own explanation for his excommunication may have some merit.

To his mind, modern-day science is a sluggish beast that isn't ready for the world-changing questions he's asking about global warming and mind reading. "I am playing by what I consider to be the rules that have worked pretty well for science over the last four centuries," Mullis says. "You make observations, write theories to fit them, try experiments to disprove the theories and, if you can't, you've got something."

When he applies these rules to certain topics he finds interesting, people don't get it.

But come on, astral travel?

"Look at any notion that 19th century scientists held as unassailable truth about the universe," Mullis retorts. "Anything: the nature of light, energy, matter, time, space. How silly those ideas, how wrong they are to us now."

It is true: Einstein's relativity shows that matter curves space and that time slows down when you speed up -- concepts that Newton would have found more absurd than the existence of angels. One major reason we progressed past the absurdities to what we now call truth was the adherence to scientific equipoise -- the concept that requires scientists, in the face of the unknown, to consider all possible explanations. So if astral planes and global warming are open questions (arguably they are), then the out-of-hand dismissal of Mullis demonstrates a lack of equipoise. Scientists therefore make a cultural decision, not a scientific one, when they marginalize Mullis as a fool.

Mullis identifies the cultural decision this way: "Science has not been successful by making up explanations of things that fit with the current social fabric." But modern science, supported by taxpayer money and held accountable to a press and a public, is compelled to fit the social norm. It cannot afford to step out on limbs of revolutionary thought (though arguably it does -- look at string theory). Mullis considers himself a revolutionary, laughed at by those who will only cling to the trunk of the tree.

No wonder they don't like him, and they certainly won't accept that reading of his ostracism. In part because of this ostracism, and in part because of his own love of other things -- from surfing to LSD to writing to his new wife -- Mullis has not done much new science since PCR.

But he told me he is involved in a new start-up that is using compact disc technology to read genes in blood. He could not tell me much about it for proprietary reasons, but the idea is that you could smear a little blood on a disc and read the genes there in a CD player. This technology will have to go head-to-head with the "gene chip" technologies already far into testing phases. The bedside genetic analysis of patients these technologies offer would bring about a revolution in medicine as large as PCR has already wrought.

Whether it will be Mullis who does it -- a second time -- remains to be seen.

By William Speed Weed

William Speed Weed is a freelance writer and radio producer living in San Francisco.

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